The overall objective of this research is to elucidate the cellular and molecular basis of one or more stages which must occur during progression to malignancy in response to chemical carcinogens and tumor promoters. Rational approaches to prevention of one or more stages of progression is another long term goal. Recently published or in press results from our laboratory indicate that late stage tumor promotion by phorbol esters occurs by a process involving induction of a new phenotype (vs. selection of a preexisting variant). The mechanism appears not to require mitogenic stimulation or ornithine decarboxylase induction by the promoter. Promoter induced changes in cell surface glycoconjugate synthesis as well as chromosome and chromatid breaks and rearrangements occur and are being investigated for their role in promotion of tumor cell phenotype. Retinoids inhibit phorbol ester promotion in this system and are being used to investigate 1) required events in promotion and 2) cancer prevention.